Pharmacodynamics of tigecycline alone and in combination with colistin against clinical isolates of multidrug-resistant Acinetobacter baumannii in an in vitro pharmacodynamic model.

Abstract

The objectives of this study, which were based on the hypothesis of mutant prevention concentration (MPC), were to compare tigecycline and colistin monotherapy and combination therapy against multidrug-resistant Acinetobacter baumannii (MDR-AB) and to identify changes in the susceptibility of the organism using an in vitro pharmacodynamic model. Human free-drug concentration profiles of colistin and tigecycline used alone and in combination were simulated against four clinical MDR-AB isolates over 24 h. Pharmacodynamic activity was measured as log10 CFU/mL and as the area under the bactericidal curve (AUBC). The minimum inhibitory concentration (MIC) for all isolates was determined in triplicate by the broth microdilution method. All isolates grew to control levels in the tigecycline and colistin monotherapy conditions, and the combination of colistin plus tigecycline 100 mg every 12 h (q12h) or 50 mg q12h achieved a greater reduction in bacterial density than colistin alone (-2.65 ± 1.73 or -2.09 ± 1.47 vs. 0.98 ± 0.64 log10 CFU/mL; P <0.01). Likewise, both combinations significantly reduced the AUBC compared with that achieved using colistin alone (106.9 ± 24.5 or 117.7 ± 23.5 vs. 168.1 ± 14.2 log10 CFU⋅h/mL; P <0.05). When tigecycline or colistin monotherapy concentrations were below MPC, tigecycline MICs increased 4-32-fold and colistin MICs increased >16-fold. No loss in susceptibility to tigecycline was found with combination therapy. A combination of tigecycline (high dose) and colistin may be an effective therapy to synergistically prevent the emergence of resistance during treatment of MDR-AB (tigecycline MIC < 2 mg/L) infections.